Showing papers by "Sang Won Suh published in 2018"

Effects of Protocatechuic Acid (PCA) on Global Cerebral Ischemia-Induced Hippocampal Neuronal Death

Abstract: Global cerebral ischemia (GCI) is one of the main causes of hippocampal neuronal death. Ischemic damage can be rescued by early blood reperfusion. However, under some circumstances reperfusion itself can trigger a cell death process that is initiated by the reintroduction of blood, followed by the production of superoxide, a blood–brain barrier (BBB) disruption and microglial activation. Protocatechuic acid (PCA) is a major metabolite of the antioxidant polyphenols, which have been discovered in green tea. PCA has been shown to have antioxidant effects on healthy cells and anti-proliferative effects on tumor cells. To test whether PCA can prevent ischemia-induced hippocampal neuronal death, rats were injected with PCA (30 mg/kg/day) per oral (p.o) for one week after global ischemia. To evaluate degenerating neurons, oxidative stress, microglial activation and BBB disruption, we performed Fluoro-Jade B (FJB), 4-hydroxynonenal (4HNE), CD11b, GFAP and IgG staining. In the present study, we found that PCA significantly decreased degenerating neuronal cell death, oxidative stress, microglial activation, astrocyte activation and BBB disruption compared with the vehicle-treated group after ischemia. In addition, an ischemia-induced reduction in glutathione (GSH) concentration in hippocampal neurons was recovered by PCA administration. Therefore, the administration of PCA may be further investigated as a promising tool for decreasing hippocampal neuronal death after global cerebral ischemia.

Effects of glycemic variability and hyperglycemia in acute ischemic stroke on post-stroke cognitive impairments

Abstract: Aims We aimed to investigate the effect of glycemic variability in the acute stage of stroke on the development of post-stroke cognitive impairment (PSCI). Methods Patients who underwent blood glucose tests at least five times within 7 days after acute ischemic stroke were included. Factors related to glycemic variability (standard deviation (SD), coefficient of variance (CV), and mean absolute glucose (MAG)) were calculated; neuropsychological assessments were administered 3 months after stroke. PSCI was defined as a score of less than −2 SDs for age-, sex-, and education-adjusted means in at least one cognitive domain. Results A total of 354 patients were enrolled. PSCI was identified in 74 (20.9%) subjects. In the diabetic group (n = 87), MAG was a significant predictor for PSCI (adjusted OR, 1.94; 95% CI, 1.11–3.42); however, it was not significant in the non-diabetic group, although PSCI exhibited an increasing tendency within higher SD and MAG tertiles. Moreover, hyperglycemia demonstrated a detrimental effect on PSCI, regardless of diabetes status; this effect did not appear in poorly-controlled diabetic patients with HbA1c ≥ 8.0%. Conclusions Glycemic variability and hyperglycemia during acute ischemic stroke were identified as novel predictors for PSCI. Although this result is not evidence of a causal relationship, our study suggests that monitoring glycemic index and controlling its variability during the acute phase of ischemic stroke may help to prevent poor cognitive outcomes.

Human Placenta-Derived Mesenchymal Stem Cells Reduce Mortality and Hematoma Size in a Rat Intracerebral Hemorrhage Model in an Acute Phase.

Abstract: Intracerebral hemorrhage (ICH) is a critical disease, highly associated with mortality and morbidity. Several studies have demonstrated the beneficial effect of mesenchymal stem cells (MSCs) on ICH, mostly focused on their mid-to-long-term effect. Acute hematoma expansion is one of the most important prognostic factors of ICH. We hypothesized that MSCs would decrease mortality and hematoma size in acute ICH, based on the findings of a few recent researches reporting their effect on blood-brain barrier and endothelial integrity. Rat ICH models were made using bacterial collagenase. One hour after ICH induction, the rats were randomly divided into MSC-treated and control groups. Mortality, hematoma volume, ventricular enlargement, brain edema, and degenerating neuron count were compared at 24 hours after ICH induction. Expression of tight junction proteins (ZO-1, occludin) and coagulation factor VII mRNA was also compared. Mortality rate (50% versus 8.3%), hematoma size, ventricular size, hemispheric enlargement, and degenerating neuron count were significantly lower in the MSC-treated group (p = 0.034, 0.038, 0.001, 0.022, and <0.001, resp.), while the expression of ZO-1 and occludin was higher (p = 0.007 and 0.012). Administration of MSCs may prevent hematoma expansion in the hyperacute stage of ICH and decrease acute mortality by enhancing the endothelial integrity of cerebral vasculature.

Zinc Promotes Adipose-Derived Mesenchymal Stem Cell Proliferation and Differentiation towards a Neuronal Fate.

Abstract: Zinc is an essential element required for cell division, migration, and proliferation. Under zinc-deficient conditions, proliferation and differentiation of neural progenitors are significantly impaired. Adipose-derived mesenchymal stem cells (AD-MSCs) are multipotent stem cells that can differentiate into neurons. The aim of this study was to evaluate the effect of zinc on AD-MSC proliferation and differentiation. We initially examined the effect of zinc on stem cell proliferation at the undifferentiated stage. AD-MSCs showed high proliferation rates on day 6 in 30 μM and 100 μM of ZnCl2. Zinc chelation inhibited AD-MSC proliferation via downregulation of ERK1/2 activity. We then assessed whether zinc was involved in cell migration and neurite outgrowth during differentiation. After three days of neuronal differentiation, TUJ-1-positive cells were observed, implying that AD-MSCs had differentiated into early neuron or neuron-like cells. Neurite outgrowth was increased in the zinc-treated group, while the CaEDTA-treated group showed diminished, shrunken neurites. Furthermore, we showed that zinc promoted neurite outgrowth via the inactivation of RhoA and led to the induction of neuronal gene expression (MAP2 and nestin) in differentiated stem cells. Taken together, zinc promoted AD-MSC proliferation and affected neuronal differentiation, mainly by increasing neurite outgrowth.

Inhibition of NADPH Oxidase Activation by Apocynin Rescues Seizure-Induced Reduction of Adult Hippocampal Neurogenesis

Abstract: Apocynin, also known as acetovanillone, is a natural organic compound structurally related to vanillin. Apocynin is known to be an inhibitor of NADPH (Nicotinamide adenine dinucleotide phosphate) oxidase activity and is highly effective in suppressing the production of superoxide. The neuroprotective effects of apocynin have been investigated in numerous brain injury settings, such as stroke, traumatic brain injury (TBI), and epilepsy. Our lab has demonstrated that TBI or seizure-induced oxidative injury and neuronal death were reduced by apocynin treatment. Several studies have also demonstrated that neuroblast production is transiently increased in the hippocampus after seizures. Here, we provide evidence confirming the hypothesis that long-term treatment with apocynin may enhance newly generated hippocampal neuronal survival by reduction of superoxide production after seizures. A seizure was induced by pilocarpine [(25 mg/kg intraperitoneal (i.p.)] injection. Apocynin was continuously injected for 4 weeks after seizures (once per day) into the intraperitoneal space. We evaluated neuronal nuclear antigen (NeuN), bromodeoxyuridine (BrdU), and doublecortin (DCX) immunostaining to determine whether treatment with apocynin increased neuronal survival and neurogenesis in the hippocampus after seizures. The present study indicates that long-term treatment of apocynin increased the number of NeuN+ and DCX+ cells in the hippocampus after seizures. Therefore, this study suggests that apocynin treatment increased neuronal survival and neuroblast production by reduction of hippocampal oxidative injury after seizures.

Protective Effects of Protocatechuic Acid on Seizure-Induced Neuronal Death

Abstract: Protocatechuic acid (PCA) is a type of phenolic acid found in green tea and has been shown to have potent antioxidant and anti-inflammatory properties. However, the effect of PCA on pilocarpine seizure-induced neuronal death in the hippocampus has not been evaluated. In the present study, we investigated the potential therapeutic effects of PCA on seizure-induced brain injury. Epileptic seizure was induced by intraperitoneal (i.p.) injection of pilocarpine (25 mg/kg) in adult male rats, and PCA (30 mg/kg) was injected into the intraperitoneal space for three consecutive days after the seizure. Neuronal injury and oxidative stress were evaluated three days after a seizure. To confirm whether PCA increases neuronal survival and reduced oxidative injury in the hippocampus, we performed Fluoro-Jade-B (FJB) staining to detect neuronal death and 4-hydroxynonenal (4HNE) staining to detect oxidative stress after the seizure. In the present study, we found that, compared to the seizure vehicle-treated group, PCA administration reduced neuronal death and oxidative stress in the hippocampus. To verify whether a decrease of neuronal death by PCA treatment was due to reduced glutathione (GSH) concentration, we measured glutathione with N-ethylmaleimide (GS-NEM) levels in hippocampal neurons. A seizure-induced reduction in the hippocampal neuronal GSH concentration was preserved by PCA treatment. We also examined whether microglia activation was affected by the PCA treatment after a seizure, using CD11b staining. Here, we found that seizure-induced microglia activation was significantly reduced by the PCA treatment. Therefore, the present study demonstrates that PCA deserves further investigation as a therapeutic agent for reducing hippocampal neuronal death after epileptic seizures.

Carvacrol Attenuates Hippocampal Neuronal Death after Global Cerebral Ischemia via Inhibition of Transient Receptor Potential Melastatin 7

Abstract: Over the last two decades, evidence supporting the concept of zinc-induced neuronal death has been introduced, and several intervention strategies have been investigated. Vesicular zinc is released into the synaptic cleft, where it then translocates to the cytoplasm, which leads to the production of reactive oxygen species and neurodegeneration. Carvacrol inhibits transient receptor potential melastatin 7 (TRPM7), which regulates the homeostasis of extracellular metal ions, such as calcium and zinc. In the present study, we test whether carvacrol displays any neuroprotective effects after global cerebral ischemia (GCI), via a blockade of zinc influx. To test our hypothesis, we used eight-week-old male Sprague–Dawley rats, and a GCI model was induced by bilateral common carotid artery occlusion (CCAO), accompanied by blood withdrawal from the femoral artery. Ischemic duration was defined as a seven-minute electroencephalographic (EEG) isoelectric period. Carvacrol (50 mg/kg) was injected into the intraperitoneal space once per day for three days after the onset of GCI. The present study found that administration of carvacrol significantly decreased the number of degenerating neurons, microglial activation, oxidative damage, and zinc translocation after GCI, via downregulation of TRPM7 channels. These findings suggest that carvacrol, a TRPM7 inhibitor, may have therapeutic potential after GCI by reducing intracellular zinc translocation.

Combined Treatment With Dichloroacetic Acid and Pyruvate Reduces Hippocampal Neuronal Death After Transient Cerebral Ischemia.

Abstract: Transient cerebral ischemia (TCI) occurs when blood flow to the brain is ceased or dramatically reduced. TCI causes energy depletion and oxidative stress, which leads to neuronal death and cognitive impairment. Dichloroacetic acid (DCA) acts as an inhibitor of pyruvate dehydrogenase kinase (PDK). Additionally, DCA is known to increase mitochondrial pyruvate uptake and promotes glucose oxidation during glycolysis, thus enhancing pyruvate dehydrogenase (PDH) activity. In this study, we investigated whether the inhibition of PDK activity by DCA, which increases the rate of pyruvate conversion to adenosine triphosphate (ATP), prevents ischemia-induced neuronal death. We used a rat model of TCI, which was induced by common carotid artery occlusion and hypovolemia for 7 min while monitoring the electroencephalography for sustained isoelectric potential. Male Sprague-Dawley rats were given an intraperitoneal injection of DCA (100 mg/kg) with pyruvate (50 mg/kg) once per day for 2 days after insult. The vehicle, DCA only or pyruvate on rats was injected on the same schedule. Our study demonstrated that the combined administration of DCA with pyruvate significantly decreased neuronal death, oxidative stress, microglia activation when compared with DCA, or pyruvate injection alone. These findings suggest that the administration of DCA with pyruvate may enhance essential metabolic processes, which in turn promotes the regenerative capacity of the post-ischemic brain.

Acetylcholine precursor, citicoline (cytidine 5′‐diphosphocholine), reduces hypoglycaemia‐induced neuronal death in rats

Abstract: Citicoline (cytidine 5'-diphosphocholine) is an important precursor for the synthesis of neuronal plasma membrane phospholipids, mainly phosphatidylcholine. The administration of citicoline serves as a choline donor for the synthesis of acetylcholine. Citicoline has been shown to reduce the neuronal injury in animal models with cerebral ischaemia and in clinical trials of stroke patients. Citicoline is currently being investigated in a multicentre clinical trial. However, citicoline has not yet been examined the context of hypoglycaemia-induced neuronal death. To clarify the therapeutic impact of citicoline in hypoglycaemia-induced neuronal death, we used a rat model with insulin-induced hypoglycaemia. Acute hypoglycaemia was induced by i.p. injection of regular insulin (10 U kg-1 ) after overnight fasting, after which iso-electricity was maintained for 30 minutes. Citicoline injections (500 mg/kg, i.p.) were started immediately after glucose reperfusion. We found that post-treatment of citicoline resulted in significantly reduced neuronal death, oxidative injury and microglial activation in the hippocampus compared to vehicle-treated control groups at 7 days after induced hypoglycaemia. Citicoline administration after hypoglycaemia decreased immunoglobulin leakage via blood-brain barrier disruption in the hippocampus compared to the vehicle group. Citicoline increased choline acetyltransferase expression for phosphatidylcholine synthesis after hypoglycaemia. Altogether, the present findings suggest that neuronal membrane stabilisation by citicoline administration can save neurones from the degeneration process after hypoglycaemia, as seen in several studies of ischaemia. Therefore, the results suggest that citicoline may have therapeutic potential to reduce hypoglycaemia-induced neuronal death.

EAAC1 gene deletion reduces adult hippocampal neurogenesis after transient cerebral ischemia.

Abstract: Several studies have demonstrated that excitatory amino acid carrier-1 (EAAC1) gene deletion exacerbates hippocampal and cortical neuronal death after ischemia. However, presently there are no studies investigating the role of EAAC1 in hippocampal neurogenesis. In this study, we tested the hypothesis that reduced cysteine transport into neurons by EAAC1 knockout negatively affects adult hippocampal neurogenesis under physiological or pathological states. This study used young mice (aged 3–5 months) and aged mice (aged 11–15 months) of either the wild-type (WT) or EAAC1 −/− genotype. Ischemia was induced through the occlusion of bilateral common carotid arteries for 30 minutes. Histological analysis was performed at 7 or 30 days after ischemia. We found that both young and aged mice with loss of the EAAC1 displayed unaltered cell proliferation and neuronal differentiation, as compared to age-matched WT mice under ischemia-free conditions. However, neurons generated from EAAC1 −/− mice showed poor survival outcomes in both young and aged mice. In addition, deletion of EAAC1 reduced the overall level of neurogenesis, including cell proliferation, differentiation, and survival after ischemia. The present study demonstrates that EAAC1 is important for the survival of newly generated neurons in the adult brain under physiological and pathological conditions. Therefore, this study suggests that EAAC1 plays an essential role in modulating hippocampal neurogenesis.

Antimicrotubule Agent-Induced Zinc Neurotoxicity.

Abstract: Colchicine or vincristine depolymerize microtubules, an action which blocks neuron axonal transport. Thus, these chemicals showed selective neurotoxicity in hippocampal neurons. However, the mechanism of neurotoxicity by these antimicrotubule agents has remained unclear. Our previous studies have suggested that colchicine-induced hippocampal neuron death is caused by incremental increases in intraneuronal free zinc. We have demonstrated that zinc transporter 3 gene deletion (ZnT3-/-) reduces dentate granule cell death after colchicine injection. This ZnT3-/--mediated reduction of dentate granule cell death was accompanied by a decrease in the incidence of oxidative injury. Unexpectedly, we found that ZnT3-/- mice contain a higher glutathione (GSH) level in the hippocampal neurons than wild type mice. Thus, ZnT3-/- mice showed less neuronal GSH depletion by colchicine injection, and thus less neuronal death. These results suggest that the higher levels of neuronal GSH in ZnT3-/- mice result in less dentate granule cell death after colchicine injection. In addition to colchicine, our lab also demonstrated that a chemotherapeutic agent, pacritaxel (Taxol), which is a microtubule stabilizing agent, depleted vesicular zinc in the presynaptic terminals and induced a reduction of neurogenesis. Therefore, in the present review, we discussed how antimicrotubule agent-induced neurotoxicity and cognitive impairment is associated with zinc dyshomeostasis in the brain.

Clinical Meaning of the Ratio of Brachial Pre-Ejection Period to Brachial Ejection Time in Patients with Left Ventricular Systolic Dysfunction.

Abstract: An increase in the ratio of the brachial pre-ejection period to brachial ejection time [pre-ejection period (PEP)/ET] is correlated with a decrease of left ventricular ejection fraction (LVEF). The current study was designed to test the hypothesis that the change value (Δ) of PEP/ET is a useful indicator of Δ LVEF in patients with left ventricular systolic dysfunction.We consecutively enrolled 104 patients with left ventricular systolic dysfunction (LVEF < 45%). PEP/ET, B-type natriuretic peptide (BNP), and LVEF were evaluated at baseline and at 6-month follow-up. Compared with the baseline measurements, the 6-month values of ΔLVEF, ΔBNP, and ΔPEP/ET were 9.8% ± 9.0% (from 36.3% ± 9.2% to 46.3% ± 12.5%, P < 0.001), -168.5 ± 255.4 (from 271.4 ± 282.5 to 104.1 ± 129.6, P < 0.001), and -0.060 ± 0.069 (from 0.413 ± 0.097 to 0.358 ± 0.079, P < 0.001), respectively. There were significant correlations between LVEF and PEP/ET and between LVEF and BNP in both the initial (r = -0.316, P = 0.001 and r = -0.598, P < 0.001, respectively) and 6-month follow-up (r = -0.307, P = 0.003 and r = -0.701, P < 0.001, respectively). The Steiger's Z test showed that BNP had a significantly stronger correlation with LVEF compared with the correlations between LVEF and PEP/ET in both the initial and 6-month studies (Z = 2.471, P = 0.013 and Z = 3.575, P < 0.001, respectively). There were also significant correlations between ΔLVEF and ΔPEP/ET (r = -0.515, P < 0.001) and between ΔLVEF and ΔBNP (r = -0.581, P < 0.001); however, there was no difference between the correlations for ΔLVEF and ΔPEP/ET versus ΔLVEF and ΔBNP (Steiger's Z = 0.600, P = 0.545).In patients with left ventricular systolic dysfunction not only ΔBNP but also ΔPEP/ET could be a simple indicator of predicting change of LVEF.